Unravelling Variability in Antidepressant Outcomes using Pharmacogenetic and Pharmacokinetic Strategies

Genetic factors play a significant role in the interindividual variability of antidepressant response. This PhD thesis comprises three studies that investigate how genetic variations influence antidepressant treatment outcomes. The first study analyzed data from the STOP-PD II trial (N = 171), where participants with psychotic depression were treated with sertraline and olanzapine for up to 20 weeks, followed by a randomized phase of 36 weeks when participants received sertraline and olanzapine or sertraline and placebo. Using genome-wide association studies (GWAS), we identified suggestive genomic associations for remission. When using polygenic risk scores (PRS), we found associations between remission and PRS for antidepressant response, as well as between relapse and PRS for Alzheimer’s disease. These findings provide insights into the genetic architecture of treatment outcomes in psychotic depression. The second study focused on pharmacokinetic factors, leveraging data from the IRL-GRey study (N = 325), where older adults with depression were treated with venlafaxine (VEN) for 12 weeks. We adapted and improved a population pharmacokinetic model for VEN and its active metabolite, O-desmethylvenlafaxine (ODV). Incorporating CYP2D6 metabolizer status significantly enhanced the model’s predictive accuracy. CYP2D6 metabolizers showed different VEN clearance, VEN exposure, and active moiety (VEN plus ODV) exposure, where differences were mostly driven by CYP2D6 poor metabolizers. The study highlights the importance of CYP2D6 metabolizer status in optimizing VEN dosing strategies. Using the pharmacokinetic data deriving from our model, the third study examined the relationship between VEN exposure and clinical outcomes in the same sample. Higher exposures to VEN, ODV, and its active moiety were associated with an increased risk of adverse effects, particularly nausea/vomiting and orthostatic dizziness. The findings underscore the clinical relevance of pharmacokinetic monitoring to minimize antidepressant adverse effects in older adults with depression. Together, the three studies underscore the critical role of pharmacogenetics and pharmacokinetics in advancing precision psychiatry. By elucidating the genetic and pharmacokinetic factors influencing antidepressant treatment outcomes, the thesis provides a foundation for optimizing and personalizing pharmacotherapy for depression.

Department dc:contributor.department

Pharmacology

Year dc:date.issued

2025

Author dc:creator

• Men, Xiaoyu

Advisor dc:contributor.advisor

• Mueller, Daniel J

• depression
• pharmacogenetics
• pharmacokinetics
• precision psychiatry

Handle dc:identifier.uri

https://hdl.handle.net/1807/150657

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/150657